Assessment of hepatocellular carcinoma treatment response with LI-RADS: a pictorial review

This category is assigned when the treatment response cannot be evaluated due to poor image quality or inadequate technique (e.g., failure to obtain the required phases).

The nonviable category should be assigned to treated lesions with no perceived enhancement or demonstrating only expected posttreatment enhancement patterns. The latter may depend on the applied locoregional treatment used and the time interval after treatment.

This category is applied to treated observations that cannot be confidently categorized as viable or nonviable due to overlapping enhancement features in the absence of technical or patient-related limitations.

The viable category should be assigned to treated observations with nodular, masslike, or thick irregular regions of arterial phase hyperenhancement (APHE), washout appearance, or enhancement similar to pretreatment tumor. These features indicate the presence of viable tumor cells with high certainty. This is valid for all locoregional treatments with the exception of radiation therapy as discussed further.

It is important to note that these LR-TR categories are assigned based on perceived probabilities of macroscopic tumor viability at imaging. They are not intended to reflect microscopic tumor viability visible only at histology. Thus, LR-TR Nonviable means there is no imaging evidence of gross viable tumor, but it does not exclude the presence of viable tumor cells visible microscopically on histology slides obtained from tissue sampling.

The most common locoablative therapies for HCC are percutaneous ethanol ablation (PEA), radiofrequency ablation (RFA), and microwave ablation (MWA).

Percutaneous ethanol ablation, a chemical ablation procedure, was the first locoablative therapy used clinically for treating early-stage HCC. In this technique, one or more needles are inserted percutaneously into the tumor under image guidance (Fig. 4). Absolute ethanol is injected into the tumor, in a volume ranging from 1 to 10 mL depending on the tumor size. Ethanol is cytotoxic and upon entering the tumor microcirculation causes coagulation necrosis via platelet aggregation, small vessel thrombosis, and ischemia [8]. With PEA, tumor targeting may be difficult as the ablated tumor margins are less clearly identified during the procedure [9]. To overcome this issue, two treatment sessions per week for up to 12 sessions may be required to induce complete tumor necrosis [10, 11].

RFA and MWA are more recently developed therapies. As opposed to the cytotoxic effect of PEA, RFA and MWA rely on heat to damage and to kill cells. Heat-induced damage and death of HCC and surrounding hepatocytes is proportional to temperature and exposure time [12]. Cellular damage occurs in 60 min at 46 °C, while cell death occurs in 4–6 min at 50–52 °C and is nearly instantaneous between 60 and 100 °C [13]. Coagulative necrosis is the main cell death mechanism. However, when the delivered energy is insufficient, for example, towards the periphery of the ablation zone, a transition is observed from necrosis to apoptosis [14]. The energy is deposited into the tissue using percutaneously inserted needle-like elements known as “applicators” [6]. Based on the physical principles behind each technique, the applicator in RFA is also termed an electrode while the applicator in MWA is also termed an antenna. The applicators are inserted percutaneously under imaging guidance; they can be straight or expandable, and they can be used alone or in clusters.

RFA is currently indicated to treat tumors up to about 3 cm in size (Fig. 5). To achieve proper energy delivery and tumoral ablation, one to three applicators are advanced through the tumor and at least 5 mm beyond its deepest margin. Alternating current within the radiofrequency spectrum (between 300 and 500 kHz) is delivered to a closed-circuit between two electrodes: the applicator in the tumor and a grounding pad positioned on the skin far from the ablation site (e.g., on the thighs). The resistive effect around the noninsulated applicator tip heats the tissue in a centrifugal direction [13]. Temperatures as high as 105 °C can be achieved, which boils, vaporizes, necroses, and chars the tissue [13]. The charring has the unintended consequence of increasing tissue impedance, which limits the transmission of energy to adjacent cells thus reducing RFA efficacy. Some internally cooled applicators alternate between periods of high and low energy deposition which partially offsets the impedance effect [15]. Another limiting factor of RFA is the “heat sink effect” that reduces treatment efficacy for perivascular tumors due to heat loss into large vessels [16, 17]. For tumors adjacent to large vessels alternative therapies may be preferable. Procedure time generally ranges from 10 to 16 min per tumor depending on its size.

MWA is similar to RFA as one or more needle-like applicators are inserted percutaneously into the tumor using image guidance (Fig. 6). Grounding pads are unnecessary, which simplifies the setup and eliminate the risk of grounding pad burns. MWA is achieved by generating a rapidly oscillating magnetic field around the applicator (antenna) at 900 MHz to 2450 MHz, frequencies 3000 to 5000 times greater than RFA [18]. Unlike RFA where resistive forces are predominant, friction is the main energy delivery mechanism in MWA. The oscillating electromagnetic field causes water and other polar molecules to flip billions of time per seconds, which heats tissues around the noninsulated tip of the applicator [18]. The electromagnetic field created by MWA is not affected by tissue boiling and charring and the deposited energy is too intense to be dissipated by flowing blood [19]. Additionally, simultaneous multi-probe ablation act synergistically to create a larger ablation zone than sequential single-probe ablation [19]. For these reasons, MWA achieves higher intratumoral temperatures faster, more uniformly, and over a larger volume than RFA; takes less time to perform (under 10 min per tumor); and can be used to treat larger tumors as well as tumors adjacent to large vessels.

Ablative therapies can damage blood vessels and bile ducts, potentially resulting in hematomas and bilomas within or immediately adjacent to the ablation zone. Small arterioportal shunts may be induced by the procedure in up to 25% of cases; the vast majority heal spontaneously at 1–4 months follow-up [17, 20]. Additionally, the parenchyma along the ablation margin and in the surrounding liver may become hyperemic; the hyperemia typically resolves after about 6 months. Complications post locoablative therapies are infrequent (2–3%) and are similar for PEA, RFA, and MWA: hemorrhage, infection, abscess, visceral organ injury, bile leak, liver failure, portal vein thrombosis, cardiac arrythmias, and pneumothorax [17, 20]. Risk of tumor seeding (0.5–3%) can be reduced during RFA and MWA by cauterization of the needle trajectory at the time of probe removal and by avoiding direct puncture of subcapsular tumors [21]. Serious skin burns (0.2%) at the grounding pad site are an uncommon and unique complication associated with RFA; these have become rare with technical advancements [22].

Although PEA is simple, safe, and inexpensive, it has a practical drawback due to multiple treatment sessions and a prolonged treatment time [23]. Randomized controlled trials have shown the superiority of RFA compared to PEA in local control and tumor recurrence [10, 11, 24, 25]. PEA is typically used when thermal methods are at higher risks of complication or reduced efficacy due to tumor proximity to major bile ducts, large vessels, liver capsule, abdominal organs, and heart.

RFA is considered the first line of treatment in non-surgical patients for HCC under 3 cm [26‐28]. Randomized controlled trials have shown inconsistent results comparing long-term survival between patients undergoing RFA versus hepatic resection [29]. However, RFA is less invasive, has fewer complications, has less impact on hepatic reserve, requires shorter hospitalization, and is less expensive than surgery [26‐28]. While RFA remains the standard of care for locoregional therapy of non-surgical patients and early-stage HCC [30, 31], MWA shows promising results for local control and survival and has already been implemented in many institutions. No published study has confirmed superiority of MWA to RFA: both techniques have been shown to have low recurrence rate at 2 years in a recent randomized controlled trial for up to three tumors < 4 cm in size [32].

Posttreament appearance after PEA, RFA, and MWA is similar but non-identical and depends on the time interval after therapy. At first posttreament follow-up, typically 1–3 months, the ablation zone should encompass the entire tumor volume and as well as the surrounding hepatic parenchyma along the tumor margin. The anticipated diameter of the ablation zone for RFA and MWA is typically 5 to 10 mm greater than the treated tumor [33]. With PEA, the ablation zone volume is harder to predict; margins may be the same size or larger than the tumor. Attenuation and signal intensity of the ablation zone are variable. Heterogeneous hyperdensity/intensity on unenhanced CT or T1-weighted MRI can be seen, reflecting coagulative necrosis. The ablation zone is typically hypointense on T2-weighted MRI except for portions liquefied by necrosis or containing fluid collections (bilomas, hematomas). With RFA and MWA, due to tract cauterization, a needle trajectory in the hepatic parenchyma towards the tumor is often seen. The ablation zone may contain gas foci for up to a month posttreatment. In the majority of asymptomatic patients, these reflect air introduced by the needles during the procedure or tissue necrosis rather than infection [34, 35].

The attenuation and intensity of viable tumor may be indistinguishable from successfully ablated tissue, and contrast-enhanced imaging is essential to evaluate viability or recurrence [36]. Uniform thin peripheral enhancement along ablation margin and a smooth rind of parenchymal enhancement around ablation zone may be present in the first 6 months due to reactive hyperemia [8]. By 6 months, the ablation zone begins to involute, although a residual ablation zone can persist indefinitely, and marginal enhancement begins to resolve. Wedge-shaped areas of transient hepatic attenuation/intensity difference can be seen adjacent to the ablation zone due to posttreatment arterioportal shunts especially in the first 4 months. These perfusion variants can be distinguished from residual viable tumor by their geographic shape and absence of mass effect, washout appearance, or capsule appearance.

At any point posttreatment, presence of nodular APHE, washout appearance, or enhancement similar to pretreatment suggests recurrence or residual viable tumor.

The expected treatment response appearances after PEA, RFA, and MWA are summarized in Fig. 7. LR-TR nonviable, equivocal, and viable representative CT and MRI cases after PEA (Figs. 8, 9, and 10), RFA (Figs. 11, 12, and 13), and MWA (Figs. 14, 15, and 16) are provided.

Blood supply of progressed HCC is primarily arterial [37]. Transcatheter delivery of embolic material is intended to selectively obstruct arterial inflow to tumor and induce ischemia and necrosis (Fig. 17). The embolic material may be bland or may contain chemotherapy or radioactive particles. Although arterial supply of a liver segment is compromised after embolization, a patent portal axis compensates hepatocytes perfusion thus reducing damage to healthy liver. Transarterial embolization in the setting of portal thrombosis or invasion is relatively contraindicated although it can be performed if other therapies are unavailable [38].

Four main types of transarterial treatments are used (Fig. 18):

Regardless of the transcatheter therapy type, aortic, superior mesenteric, and celiac trunk angiography is performed to assess the hepatic vasculature (including anatomical variants) and to identify potential extrahepatic vessel supplying the tumor, arterioportal shunting, and blood flow to other organs [40].

Maintenance of proximal vascular patency is important as multiple treatment sessions may be needed to refine targeting, treat concomitant lesions, or limit tumor growth [41, 42]. When an additional session is necessary, it is typically scheduled at 1 to 6 months. As there is potential for treatment-induced liver failure even without tumor progression, the benefits of additional sessions should be carefully weighted [43, 44].

Transcatheter therapies are well tolerated with 50% of patients discharged the day after treatment [45]. Post-embolization syndrome is the most common side effect (> 40% of patients) observed for as long as 7–10 days posttreatment and includes nausea, fatigue, fever, and abdominal pain [46]. Serious complications (5.6%) are usually due to ischemia of target or non-target organs and include acute liver failure, abscess formation, sepsis, and gastrointestinal bleeding.

Tumor lysis syndrome is a rare complication caused by rapid destruction of neoplastic cells. It occurs most frequently after treatment of large HCC in patients with renal insufficiency and other metabolic derangements (e.g., elevation of uric acid or phosphorous) [47]. Early recognition of this syndrome is important as delay in treatment can be life threatening (e.g., renal insufficiency, cardiac arrythmias, seizure) [47]. Thirty-day mortality is about 1% [48].

TACE, TAE, and DEB-TACE are non-curative but they may be performed for bridging, debulking, or palliation in patients with unresectable intermediate-stage HCC without vascular invasion [31]. The choice among the various transcatheter therapies is often difficult and should be patient-tailored after multidisciplinary discussion and consensus [31]. Extrinsic factors guiding treatment choice include costs, healthcare policies, and institution’s experience. Broad outline of literature guiding treatment choice is provided below.

TACE has been shown to prolong survival compared to systemic chemotherapy [43, 49]. Although DEB-TACE provides more sustained and tumor-selective drug delivery than conventional TACE [50], a recent meta-analysis did not demonstrate a survival advantage for DEB-TACE over conventional TACE [51]. TAE induces ischemia, which plays a key role in HCC treatment. The benefits of adding a chemotherapeutic agent to a bland embolic agent remains controversial. A meta-analysis concluded that TAE was as effective as TACE [52], and a recent randomized controlled trial did not find a difference in overall survival between DEB-TACE and TAE [45]. Given the high incidence of HCC and costs of chemotherapy, TAE might gain more attention in the future.

After TACE, hyperdensity on unenhanced CT reflects ethiodized oil agent deposition in and around the tumor. Intratumoral ethiodized oil distribution is a CT imaging marker of the distribution of the embolic material within the lesion and thus provides information on how well the lesion was targeted. Despite this benefit, intratumoral oil agent deposition limits assessment of tumor viability on CT because the radiopaque iodized material obscures enhancing viable tumor [30, 53]. MRI helps assess tumor viability because ethiodized oil is not particularly hyperintense on T1-weighted images and so does not mask enhancement. The density and extent of ethiodized oil retention decreases with time. Radiopaque embolic material is not usually used for TAE or DEB-TACE, and the enhancement of viable tumor is not obscured on CT or MRI after these therapies.

TACE, TAE, and DEB-TACE have similar posttreatment appearances except for possible obscuration of enhancement on CT as described above. Early posttreatment, regional hyperenhancement surrounding the tumor may be present, reflecting transient posttreatment perfusional alteration due to inflammation. Thin uniform linear rim enhancement of granulation tissue along the treated zone may persist for months to years. Size of the necrotic zone should decrease over time.

As with locoablative treatment, presence of gas foci within the treated lesion is a frequent finding at first follow-up, being reported in up to 13% of patients at 4–6 weeks follow-up [54], and is a marker of tumor necrosis. Intratumoral gas is rarely associated with abscess. However, patients with a history of bilioenteric anastomosis or sphincterotomy are at higher risks of infection especially if prophylactic antibiotherapy was not administered. A large amount of gas or gas/liquid levels within a cavity larger than the treated tumor are concerning for superinfection [54].

At any point posttreatment, the presence of nodular APHE, washout appearance, or enhancement similar to pretreatment indicates recurrence or residual viable tumor. TARE is discussed in the next section.

The expected treatment response appearances after TACE, TAE, and DEB-TACE are summarized in Figs. 19 and 20. LR-TR nonviable, equivocal, and viable representative CT and MRI cases after TACE (Figs. 21, 22, and 23) and TAE and DEB-TACE (Figs. 24, 25, and 26) are provided.

HCC is radiosensitive, which explains the underlying rationale for radiation-based therapy. Stereotactic body radiotherapy (SBRT) delivers radiation into the tumor from outside the body whereas TARE delivers internal radiation; however, the underlying cell death mechanism is the same: irreversible damage to the tumor’s vascular endothelium, causing progressive tumor necrosis and tumor size reduction which may continue even after the treatment has ended [55].

Although further randomized trials are needed, SBRT is increasingly considered a potential alternative to RFA for early-stage HCC [31, 74, 75]. SBRT is also an alternative bridging therapy. A recent retrospective study showed that SBRT provided similar overall survival to TACE and RFA [76]. Dose escalation to achieve better tumor control increases the risk of toxicity, especially in those with cirrhosis and compromised baseline liver function [77]. However, dose-response curves are not well studied for HCC. A systematic review suggests that 90% of local control can be achieved with common fractioned dose regimens [58]. Out-of-field recurrence is an important cause of disease progression [78].

TARE has shown a significant improvement in progression-free survival compared to TACE for early and intermediate-stage HCC [79]. A recent meta-analysis comparing TACE to TARE found an improved survival at 2 and 3 years in the TARE group compared to TACE [80]. Due to its potentially superior antitumoral activity, TARE is currently used in some centers for patients between intermediate and advanced-stage (larger tumors, portal vein invasion, poor candidate for TACE) or poor response post TACE [71]. TARE, among others, has also been used for downstaging patients slightly above resection criteria [81, 82]. Further trials are needed to establish whether TARE can be considered for advanced-stage HCC [31].

Posttreament imaging appearance is similar for radiation-based treatment (SBRT, TARE) but greatly differs from the locoablative and transcatheter therapies using non-radiating embolic material (TACE, TAE, DEB-TACE).

After SBRT, tumor size and enhancement may transiently increase during the first weeks posttreatment. This phenomenon, called pseudoprogression, has not been described with TARE.

After SBRT and TARE, intralesional APHE and washout commonly persists for the first 6 months but should decrease over time. Comparison with prior serial imaging is essential. Geographic and often heterogeneous parenchymal enhancement in the vascular territory of the treated tumor may represent inflammatory hyperemia, venous congestion, and/or radiation fibrosis depending on the timing of imaging after treatment, and can be difficult to differentiate from infiltrative tumor [83].

After 6 months, the treated zone shrinks as radiation fibrosis progresses and APHE and washout usually resolve. Late venous enhancement in the irradiated non-tumorous parenchyma may still be observed after 6 months due to parenchymal fibrosis, along with capsular retraction and biliary dilation. Washout may help differentiate radiation-induced changes from tumor progression [59].

Intralesional enhancement and washout appearance may persist for several months but eventually regress. An increase in enhancement or in washout appearance after an initial favorable response suggests recurrence.

The expected treatment response appearances after SBRT and TARE are summarized in Fig. 28. LR-TR nonviable, equivocal, and viable representative CT and MRI cases after SBRT (Figs. 29, 30, and 31) and TARE (Figs. 32, 33, and 34) are provided.